The present invention relates to novel compounds that are useful in pharmaceutical applications for inhibiting the function of proteins. More specifically, the present invention relates to inhibitors of both of matrix metalloproteinase and tumor necrosis factor.
Matrix metalloproteinases (MMPs) is constituted of at least 28 zinc-containing proteolytic enzymes that play an integral role in the physiology of the extracellular matrix (ECM). MMPs play a major role in the degradation of basement membrane and the remodeling of ECM. Certain normal physiological processes such as fetal development, inflammatory cell migration, wound healing and angiogenesis depend on the regulated activity of MMPs and natural tissue inhibitors of metalloproteinases (TIMPs). In pathological processes, such as the development of cancer, tissue-specific MMPs may be recruited to permit primary tumor growth and then the development of metastatic diseases. Activation of these MMPs has been implicated in tissue invasiveness, metastases and angiogenesis. Thus, MMP inhibition offers novel and alternative therapy to current treatment for many different types of cancer (Johnson, L. J., Dyer, R., and Hupe, D. J. Matrix Metalloproteinases. Current Opinion in Chemical Biology; 1998.2: 466-471 (1998)).
There are three distinct classes of MMPs divided by their target: collagenases (MMP-1, MMP-8, and MMP-13), stromelysins (MMP-3, MMP-10, MMP-11), and gelatinases (MMP-2 and MMP-9). MMPs are secreted into the ECM in their proenzyme form, which requires activation by other enzymes. One class of the activators is the enzyme membrane type MMP (MT-MMP). The MT-MMPs (MMP-14, MMP-15, MMP-16, MMP-17) have a transmembrane domain and are essential in the activation of pro-MMP.
Among the MMPs as mentioned above, certain MMPs (MMP-2 and MMP-9) are correlated and their over-expression has been evaluated extensively in different kinds of tumors, such colon, gastric, head and neck, prostate, and lung cancer. For example, studies showed that in colorectal cancer, both MMP-2 and MMP-9 (in both their proenzyme and active forms) were over-expressed in cancerous tissue when compared with the normal mucosa. Similar findings had been shown in gastric cancer and pancreatic cancer (Gress T. M., Muller-Pillasch F., Lerch, M. M., et al. Expressioin and in-situ localization of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in pancreatic cancer. Int. J. Cancer 1995, 62:407-413; Normura H, Sato H. Seiki M. et al. Expression of membrane type-matrix metalloproteinase in human gastric cancinomas. Cancer Res 1995; 55:3263-3266; Parsons S L, Watson S A, Brown P D, et al. Matrix metalloproteinases. Br. J. Surg. 1997, 87: 160-166). Over-expression of MMP-2 and MMP-9 was also correlated with tumor stage, tumor aggressiveness and poor prognosis for gastrointestinal, cervical, bladder and lung tumors (Nuovo G J, MacConnell P B, Simisir A, et al. Correlation of the in situ detection of polymerase chain reaction-amplified metalloproteinase complementary DNA and their inhibitors with prognosis in cervical carcinoma., Cancer Res. 1995, 55: 267-275; Davies B, Wasman J, Wasan H, et al.). Levels of matrix metalloproteinases in bladder cancer were correlated with tumor grade and invasion (Cancer Res. 1993, 53: 5365-5369; Brown P D, Bloxidge R E, Stuart N S, et al.). Association between expression of activated 72-kilodalton gelatinase and tumor spread in non-small cell lung carcinoma existed (J. Natl. Cancer Inst. 1993, 85: 574-578). Although there was clear over-expression of MMP in certain tumors, there was variability of over-expression of MMP in different tumor types. For example, Fieberg, et al. studied expression patterns of MMP-2, MMP-3, and MMP-7 in 47 human tumor xenografts, the result of which showed variable degrees of MMP-2 over-expression with 100% of soft tissue sarcomas, 84% of melanomas, 53% of testicular carcinoma and 26% of bladder cancers that exhibited MMP-2 over-expression (Fieberg H, Klostermeyer A, Schuler J B). Characterization of matrix metalloproteinases in 47 human tumor xenografts who exhibited a high expression level of MMP2 in melanomas and sarcomas (Abstract No. 3058, Proceedings of the 90th Annual Meeting of the American Association for Cancer Research. Apr. 10-13, 1999 Philadelphia (Pa.)). These results suggested that MMP-2 was a reasonable therapeutic target for these tumor.
TNFxcex1 (tumor necrosis factor-xcex1) plays an important role in the host defense. It causes resistance to many pathogenic microorganisms and some viruses. Even if TNFxcex1 has undoubtedly a beneficial function in the activation of host defense, its unregulated production (mainly on the systematic level) could lead to pathological consequences. TNFxcex1 plays a significant role in the pathogenesis of septic shock, characterized by hypotension and multiple organ failure among others. TNFxcex1 is the main mediator of cachexia characterized by abnormal weight-loss of cancer patients. Often TNFxcex1 is detected in the synovial fluid of patients suffering from arthritis. There was a broad spectrum of diseases, where TNFxcex1 could play a role. Compounds inhibiting the release of TNFxcex1 may be therefore useful in the treatment of numerous pathologies in which TNFxcex1 is involved, such as rheumatoid arthritis, Crohn""s disease, plaque sclerosis, septic shock, cancer or cachexia associated with an immunodeficiency.
One objective of the present invention is to provide a compound, 1-[3,4-dihydroxy-5-(2-hydroxyethyl)-tetrahydrofuran-2-yl]pyrimidine-2,4(1H,3H)-dione, which exhibits an inhibitory effect on matrix metalloproteinase-2 (gelatinase A) and on the binding of TNFxcex1 to TNFxcex1-RI.
Another objective of the present invention is to provide a compound having a general formula (I) for inhibiting gelatinase A 
wherein X is a Zn(II) chelating group and selected from the group consisting of (CH2)nOH, (CH2)nNH2, (CH2)nSH, (CH2)mCOOH, (CH2)mCOOR, (CH2)mCONH2, (CH2)mxe2x80x3CONHxe2x80x94OH, (CH2)mxe2x80x3CONHxe2x80x94R, and (CH2)nxe2x80x2O(PO3)mxe2x80x3(mxe2x80x3+1), wherein n=2, 3, 4, or 5, nxe2x80x2=2 or 3, m=1, 2, 3, or 4, mxe2x80x2=1, 2, 3, 4, 5, or 6, mxe2x80x3=1, 2, 3, and R=xe2x80x94Cmxe2x80x2H2mxe2x80x2+1 or aryl groups.
It should be understood that both the foregoing general description and the following detailed description are intended to provide an explanation of the invention as claimed, rather than to limit the scope of the present invention.